Metabolic engineering of lactate dehydrogenase rescues mice from acidosis

Abstract

Acidosis causes millions of deaths each year and strategies for normalizing the blood pH in acidosis patients are greatly needed. The lactate dehydrogenase (LDH) pathway has great potential for treating acidosis due to its ability to convert protons and pyruvate into lactate and thereby raise blood pH, but has been challenging to develop into a therapy because there are no pharmaceutical-based approaches for engineering metabolic pathways in vivo. In this report we demonstrate that the metabolic flux of the LDH pathway can be engineered with the compound 5-amino-2-hydroxymethylphenyl boronic acid (ABA), which binds lactate and accelerates the consumption of protons by converting pyruvate to lactate and increasing the NAD+/NADH ratio. We demonstrate here that ABA can rescue mice from metformin induced acidosis, by binding lactate, and increasing the blood pH from 6.7 to 7.2 and the blood NAD+/NADH ratio by 5 fold. ABA is the first class of molecule that can metabolically engineer the LDH pathway and has the potential to have a significant impact on medicine, given the large number of patients that suffer from acidosis.

The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect

“…We showed that in the Group Ay/a-M600, the lactate level was doubled as compared to untreated agouti-mice. However, it was below the threshold of lactate concentration (10 mM), which in rodents characterizes the development of severe forms of lactic acidosis, leading to pathological changes [ 43 , 44 ] . We also showed the absence of the cumulative effect of MF, taken at a dose of 600 mg/kg, on the plasma levels of lactate, since there were no significant differences in the lactate concentration in agouti-mice treated with MF for one and ten days.…”

A Metabolism Toolbox for CAR T Therapy

“…Reducing the potassium level through enforced expression of potassium channels in T cells can enhance their antitumor activity (122). A lactate-binding compound has been recently developed as a potent pharmaceutical approach for engineering metabolic flux of lactate and normalizing the pH in vivo (245).…”

Pyruvate is a prospective alkalizer to correct hypoxic lactic acidosis

“…It also cannot reduce but can even exacerbate the lactate accumulation [ 1 ]. Furthermore, SB has several negative side effects, such as altering blood pressure and triggering apoptosis [ 12 ]. SB administration requires a functional cardio-respiratory system to exhale the extra CO 2 and there is a trend against using it in cardiac arrest patients.…”

“…Many other agents are being investigated to better manage LA. For example, the compound 5-amino-2-hydroxymethylphenyl boronic acid, a phenyl boronic acid derivative, binds lactate and normalizes the blood pH by increasing the consumption of protons via the LDH pathway [ 12 ]. Spermidine, with its activating effect on PDH phosphatase, can also activate PDH, stimulating the decarboxylation of pyruvate and inhibiting lactate accumulation [ 1 ].…”

“…It is reported that shifting the equilibrium of the LDH pathway towards the production of more lactate results in the consumption of protons and increase of the NAD + /NADH (nicotinamide adenine dinucleotide: oxidized form/reduced form) ratio via the hydrogenation of pyruvate [ 12 ]. Pyruvate is endogenously produced during glycolysis by breaking down glucose into two three-carbon molecules.…”